Novel Methacrylate-Thiol-Ene Composites for Dental Restorative Materials As the demand for aesthetically pleasing restorative materials has increased, so has the desire and demand for improved performance. Despite their increasing prevalence, the methacrylate resin phase for the vast majority of these materials has remained largely unaltered since Bowen first proposed the materials nearly 50 years ago. Presently, composites suffer from shrinkage and stress that arise during polymerization, a subsequent lack of appropriate mechanical properties of the resin material, and low depth of cure for polymerization. The composites also generally contain in their core monomer the substituent bisphenol-A, which is associated with ever increasingly significant regulatory and health concerns. Following polymerization, the composites contain significant fractions of unreacted monomer that results in the critical presence of extractables that coupled with moisture uptake by the sample can lead to degradation. The result is often secondary cavities and premature failure where composites average lifetime is less than 8 years. High resin viscosity of the base dimethacrylate monomers limits the ability to incorporate high filler volumes without the use of low viscosity reactive diluents that generally reduce the modulus and results in higher volume shrinkage and shrinkage stress. The resin phase is comprised primarily of dimethacrylate monomers typically selected from BisGMA, BisEMA, UDMA, and TEGDMA. Classically, the limitations of these materials have involved a trade-off between the mechanical behavior, the stress and the extent of reaction/conversion of the material that limits extractables and water sorption. These trade-offs have limited the advent of significant advancements in the development and performance of new dental restorative composites as the BisGMA/TEGDMA systems have proven to be a local optimum within this overall flawed compromise. Here, we propose a methodology that synergistically combines the use of thiol-ene and methacrylate chemistries and has demonstrated feasibility for a novel new system that is entirely compatible with existing systems. The synergistic combination of both methacrylate and thiol-ene click chemistries changes the reaction paradigm and enables dramatic improvement in numerous critical areas ? lower shrinkage and stress, improved mechanics, higher extent of reaction, improved depth of cure along with the elimination of bisphenol-A, and reduced extractables and degradation. The use of alternative chemistries to the purely dimethacrylate systems that have been prevalent in dentistry since the 1960s points to a paradigm shift dental restorative materials with expected improvements in conversion, reduced degradation and improved biocompatibility and public safety, mechanics and service life. Specifically, in the first aim, we will synthesize, optimize and implement a BPA-free methacrylate-thiol-ene composite system. By appropriately designing and incorporating a novel composite methacrylate-thiol-ene dental restorative formulation, we will enable reduced shrinkage and stress, while also improving mechanical properties. Specifically, we will design and implement hyperbranched oligomeric thiol, ene, and methacrylate functionalized fillers into an optimized methacrylate-thiol-ene resin formulation to achieve further reductions in shrinkage stress while demonstrating higher performing material properties than existing commercial composites and BisGMA/TEGDMA controls. We will also demonstrate improved adhesion with existing commercial adhesive systems along with increased depth of cure and increased lifetimes through wear and fatigue testing. Our preliminary results have demonstrated a much greater mechanical property enhancement in composite methacrylate-thiol-ene systems than in the control composite BisGMA/TEGDMA systems. These results indicate that the increased conversion of methacrylate-thiol-ene systems will not only dramatically reduce the amount of extractable monomer but also enhance the interaction between the resin phase and the fillers, leading to enhanced mechanical properties. This same benefit is expected to lead to improved adhesion with the native tooth structure. In the second aim, we will demonstrate reduced levels of extraction, degradation, and improved biocompatibility in novel high conversion low stress methacrylate-thiol-ene composite dental restorative materials. The combination of dramatic improvements already demonstrated in Phase I feasibility studies and the continued performance improvements that will result from Aim I will synergistically also result in improved biocompatibility and long term performance of these materials. Specifically, we will demonstrate improved biocompatibility as measured through cytotoxicity, sensitization, and oral mucosal irritation testing. We will also demonstrate reduced extractables and degradation products through comprehensive long term degradation studies. Feasibility of material properties has been demonstrated through flexural modulus and strength, conversion, and shrinkage stress results already achieved. Additionally, feasibility of biocompatibility has been demonstrated through biofilm growth studies, degradation/extraction data, and Cytotoxicity results. In this Phase II work we will continue to formulate composite materials that achieve significant improvements in all of these areas to achieve an even greater distinction/advantage of the methacrylate-thiol-ene materials over existing commercial materials. The composite materials resultant from this Phase II work will demonstrate superior properties to existing commercial formulations in every measurable category. The synergistic combination of methacrylate and thiol-ene chemistries coupled with a novel and optimized filler system and interface will lead to improvements in mechanical properties, adhesion, wear, and fatigue that are coupled with reductions in degradation and extraction products, reduced biofilm formation, and excellent biocompatibility. Ultimately these properties will result in dental composites that exhibit dramatic improvements in clinical performance and overall lifetimes.